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23 Systemic Therapies forPancreatic Cancer
199
treatments. Clinical studies investigating the benet of tar­geted therapies and immunotherapy strategies have resulted in signicant benets in a small percentage of patients. Ongoing studies on tumor biology and tumor microenviron­ment are promising for treatment options that will yield clin­ical benet in this cancer.

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Endoscopic Biliary Drainage andAssociated Procedures Required forPatients withMalignant Biliary Strictures
HiroyukiIsayama, ToshioFujisawa, ShigetoIshii, KoTomishima, MuneoIkemura, HirotoOta, DaishiKabemura, MakoUshio, ShoTakahashi, YusukeTakasaki, AkinoriSuzuki, KoichiIto, KazushigeOchiai, andHiroakiSaito
24
Abstract
Endoscopic biliary drainage of a malignant biliary obstruction (MBO) is a common procedure, but a recog­nized standard of evaluation is lacking. To this end, the Tokyo criteria have been newly proposed and include cer­tain denitions. Recurrent biliary obstruction (RBO) is dened as stent occlusion and migration, and the time to RBO is employed rather than the duration of stent patency. For patients with distal MBO, the preoperative manage­ment has changed to incorporate new developments in neoadjuvant chemotherapies for pancreatic cancer. Self­expandable metallic stents (SEMSs) serve as the current standard. Palliative management requires long-term stent patency, and SEMS use is thus indicated. A covered SEMS serves as the standard for palliative cases with dis­tal MBO because such stents afford a time to RBO that is similar or superior to those of other stents, with a similar rate of adverse events. Furthermore, SEMSs are remov­able. However, the optimal covered SEMS is not yet available, and covered large-bore SEMSs with anti­migration and anti-reux properties remain under evalua­tion. There is currently no standard management for hilar MBO (in either the preoperative or palliative context). Recently, an inside stent placed above the papilla was reported to afford better results than those of conventional stents, but strong evidence is lacking. Endoscopic ultrasound- guided biliary drainage (EUS-BD) serves as a salvage technique when routine endoscopic retrograde
H. Isayama (*) · T. Fujisawa · S. Ishii · K. Tomishima M. Ikemura · H. Ota · D. Kabemura · M. Ushio · S. Takahashi Y. Takasaki · A. Suzuki · K. Ito · K. Ochiai · H. Saito Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan e-mail: h-isayama@juntendo.ac.jp
cholangiopancreatography fails or is difcult. Recent clinical practice guidelines for EUS-BD are becoming accepted gradually. However, dedicated devices and strong evidence of efcacy and safety are required.

24.1 Introduction

Endoscopic biliary drainage (EBD) of a malignant biliary obstruction (MBO) is a common procedure. However, the surgical strategy is affected by patient anatomy, disease char­acteristics, and overall health status. Various types of stents are available. Here, we review the various strategies and stents used for EBD of MBO in an effort to increase the effectiveness, efciency, and safety of our procedures.
24.2 The Tokyo Criteria: AStandard
Reporting System
Evaluation of the various available biliary stents is crucial. No standard criteria have been dened until recently. The rst authors (H.I) proposed the use of the Tokyo criteria for evaluating biliary stents in terms of both efcacy and safety (Table24.1) [1]. Although many different evaluations have been published, a meta-analysis is difcult given the large variations in the stents examined and the study methods. The Tokyo criteria propose the use of the phrase “recurrent bili­ary obstruction (RBO)” to dene stent occlusion and migra­tion, replacing terms such as “stent occlusion” and “stent dysfunction”. Complications are classied as RBO or other (pancreatitis, cholecystitis, and cholangitis). We propose using the time to RBO (TRBO) when evaluating stent patency. Technical and clinical successes and other items are
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_24
201
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H. Isayama et al.
Table 24.1 Factors affect the endoscopic biliary drainage
Causative disease Papillary cancer (distal stricture) Pancreatic cancer (distal stricture) Cholangiocarcinoma (distal and hilar stricture) Gallbladder cancer (distal and hilar stricture) Metastatic lymph node (distal and hilar stricture) Direct invasion of another malignant tumor (distal and hilar stricture) Hepatocellular carcinoma (hilar stricture) Metastatic liver cancer (hilar stricture) Tumor status Resectable Borderline resectable (only pancreatic cancer) Palliation Stricture location Distal Hilar (bismuth type 1–4) Anatomy affected endoscopic procedure Normal Surgically altered (B-1, B-2, Leu-en-Y) Duodenal invasion Patients’ condition Performance status (1–4) High age Frail
Table 24.2 Kinds of self-expandable metallic stent
Structure Braided type Cross wire design Hook wire design Zigzag & Spiral-Zigzag wire design Laser cut type Zigzag wire design Covering membrane Covered type (partially-, fully-covered) Uncovered type Anchoring system Flare & Square are Flare and bank Flap Other function Drug eluting Anti-reux
also dened in the Tokyo criteria. We hope that many future reports on biliary stents will employ the Tokyo criteria, as this would greatly aid meta-analyses.
24.3 Biliary Drainage inPatients withMalignant Biliary Strictures
Many factors affect selection of the procedure and stent in patients requiring EBD (Table 24.2). It is essential to con­sider the tumor type, patient’s condition, stricture location, and surgical skills available. Distal strictures are most com-
monly caused by pancreatic cancer but also by distal cholan­giocarcinoma, gallbladder and papillary cancers, and metastatic lymph nodes. Hilar strictures are caused by vari­ous malignant tumors including hilar cholangiocarcinoma, gallbladder cancer, metastatic lymph nodes, and liver metas­tases. The resectability status must be considered when developing a drainage strategy. Resectable cancers, border­line resectable cancers (requiring neoadjuvant chemother­apy/chemoradiotherapy [NAC]), and unresectable cancers require different drainage strategies and stents.
Individual patient anatomies must also be considered. It is difcult to attain the papilla if a patient presents with a surgically altered anatomy and/or duodenal tumor obstruc­tion. Device-assisted enteroscopy is required if the anat­omy is surgically altered, and percutaneous trans-hepatic biliary drainage (PTBD) is indicated for duodenal tumor obstruction. If the papilla can be accessed via the duodenal obstruction, double stenting is required (for both the duo­denal and biliary strictures). Recently, endosonography/ endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD) has become possible [2]. Finally, the perfor­mance status of the patient is used to guide the selection of one of several possible anti-cancer treatments; the perfor­mance status also affects biliary drainage, as do older age and frailty status.

24.4 The Various Stents Available

The stent is selected by reference to the stricture location, stage of the causative disease, patients’ condition, etc. Table 24.3 lists the various stents available. Basically, two stent types are used for EBD: plastic stents (PSs) and self­expandable metallic stents (SEMSs). Both straight and double- pigtail PSs are commonly employed. SEMSs may be either braided or laser-cut. Braiding varies by the wire pat­tern, which may be a cross, hook, combined cross and hook, zigzag, or spiral zigzag (Fig.24.1). Laser-cut stents feature zigzag wires. The differences described above affect the mechanical properties of SEMSs, particularly their ability to withstand radial force (RF) and axial force [3]. Some SEMSs feature a covering membrane to prevent tumor ingrowth via the stent mesh and to facilitate stent removal [4].
The Achilles’ heel of a covered SEMS is stent migration. Tumor and hyperplastic tissues invade uncovered SEMSs via the mesh, rendering the stents difcult to remove. However, the membrane prevents tumor and tissue ingrowth; therefore, covered SEMSs do not become occluded by ingrowing tis­sue and may be easily removed. Some covered SEMSs fea­ture anti-migration systems [5, 6]. However, the optimal covered SEMS is not yet available.
ac
bd
24 Endoscopic Biliary Drainage andAssociated Procedures Required forPatients withMalignant Biliary Strictures
203
Table 24.3 Evaluating items of biliary metallic stents (Modied cita-
tion from Tokyo Criteria [1]
Technical and functional success rates
Recurrent biliary obstruction (RBO)
Causes of RBO Rate of each cause Median time from the placement Early (within 30days) or late (31days or later)
Complications other than RBO
Rate of each cause Median time from
the placement
Early (within
30days) or late (31days or later)
Severity
(Table24.2)
Survival time
The incidence of RBO during the observed period. (required the description of observational time) Median time to RBO (TRBO) estimated using the Kaplan-Meier method Non-obstruction rates at the time of 3, 6 and 12months estimated using the Kaplan­Meier method Comparison using the log-rank test Occlusion
Tumor ingrowth/mucosal hyperplasia Tumor overgrowth Sludge with/without stone Food impaction Hemobilia Kinking of bile duct Others
Symptomatic migration (required any intervention)
Proximal Distal
Pancreatitis Cholecystitis Non-occlusion cholangitis Others (bleeding, ulceration, penetration,
perforation, etc.)
Complications associated with stent
placement procedure (peroration, bleeding with scope, desaturation of oxygen, aspiration pneumonia, etc.)
24.5 Preoperative Management
ofaDistal Stricture
Previously, the basic management of a preoperative distal MBO featured the use of PSs [7, 8], which can be easily placed and removed/exchanged. However, the TRBO of a PS is shorter than that of a SEMS, and thus PS placement should be performed soon after surgery. A SEMS may be indicated by pathological evaluation of the resected specimen. However, NAC has recently become indicated for patients with resect­able or borderline resectable pancreatic cancers [9]. The dura­tion of stent placement prior to surgery is thus prolonged, and the stenting strategy must be reconsidered if the patient becomes unt for surgery. Initially, a SEMS should be chosen for patients with pancreatic cancers that are resectable or bor­derline resectable [10, 11]. Both covered and uncovered SEMSs have been used, but very few comparative studies have been published. A randomized controlled trial (RCT) of covered and uncovered SEMSs placed in patients receiving NAC revealed no signicant difference in the cumulative stent patency [12]. However, the complication proles of the two groups differed. Stent migration and cholecystitis were the principal causes of complications in the covered SEMS group versus tumor ingrowth in the uncovered SEMS group. Both types of SEMSs were used, but for patients receiving NAC, over 40% of the tumors were never resected [12]. In such cases, covered SEMSs are optimal.
Critically, stent selection must be based on patient and disease status. However, NAC is not a standard therapy for patients with distal cholangiocarcinoma; PSs remain the standard.
Fig. 24.1 Basic structures of self-expandable metallic stent (SEMS). (a) Cross wire design; (b) Hook wire design; (c) Zigzag wire design; (d)
Zigzag wire design (Laser-cut type SEMS)
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24.6 Palliative Management ofDistal Strictures
A few RCTs and meta-analyses have compared PSs with SEMSs for patients with unresectable distal MBOs [1316]. The SEMSs were clearly superior, but the choice of covered versus uncovered SEMS remains controversial. Although covered SEMSs prevent tumor ingrowth via the stent mesh [4] and thus are easily removable, this renders them prone to migration. RCTs that found no superiority of covered SEMSs over uncovered SEMSs reported a high incidence of migra­tion. However, RCTs showed signicantly longer cumulative TRBOs when using covered SEMSs with anti-migration sys­tems compared with SEMSs lacking the anti-migration mod­ication [6, 17].
24.7 Eorts toProlong theTRBOs ofCovered SEMSs
Despite the introduction of anti-migration systems, the TRBOs of covered SEMSs remain inadequate. Recently, effective chemotherapies have been used to manage unre­sectable pancreatobiliary malignancies; the incidence of stent migration is thus expected to increase [18, 19]. Prevention of migration is crucial to maintain patient quality of life and to allow patients to maintain their chemotherapy schedules. We previously showed that a weak RF and che­motherapy were the principal predictors of stent migration [19, 20]. Anti-migration systems effectively prolonged the TRBO. Figure 24.2 shows the various types of covered SEMSs with anti-migration systems, which include aps, external uncovered regions, ares, and methods of enhanc­ing the RF. No system is yet ideal, and the safety of each system requires further evaluation.
Recently, a larger-diameter fully covered SEMS (FCSEMS) developed by the rst author (H.I) has become commercially available in Japan. Mukai etal. evaluated the large-bore covered SEMS (12mm in diameter); in a pilot study, the TRBO was prolonged (compared with that of a control stent); sludge accumulation in and food impaction of the new stent were slower [21]. The complications associ­ated with stent placement were acceptable. Recently, a 12-mm-diameter FCSEMS with a large are (16mm) has become commercially available in Japan, and is considered promising.
FCSEMSs with anti-reux functions (ARSEMSs) are also promising. Bacterial infection in the FCSEMS cavity attributable to reuxed duodenal contents creates biliary sludge and stones. Food impaction of the stent body and ori­ce is a prime cause of stent occlusion. In a pilot study, an ARSEMS effectively prevented food impaction soon after placement [22]. RCTs comparing a conventional FCSEMS
a
b
c
d
Fig. 24.2 Anti-migration systems of self-expandable metallic stent.
(a) Flaps; (b) Flap; (c) Flare design; (d) Square are design
with an ARSEMS yielded controversial results. Lee and Moon et al. reported that the ARSEMS exhibited a longer cumulative TRBO than that of a conventional FCSEMS, but Hamada etal. found no superiority of the ARSEMS [23, 24]. Efforts to reduce the incidence of RBO and prolong the TRBO are continuing.

24.8 Hilar Strictures (Resectable Cases)

Prior to hepatectomy, biliary drainage and portal vein embolization are standard to prevent liver dysfunction after surgery. Pre-surgical preparation includes biliary drainage of the future remnant lobe and portal vein embo­lization of the future resected lobe. Hypertrophy of the future remnant lobe and atrophy of the future resected lobe may reduce liver dysfunction after surgery. Previously,
ab
24 Endoscopic Biliary Drainage andAssociated Procedures Required forPatients withMalignant Biliary Strictures
Fig. 24.3 Side-by-side stenting for hilar cholangiocarcinoma with three slim-covered self-expandable metallic stents (6mm in a diameter). (a)
X-ray image of side-by-side stenting. (b) Endoscopic image of side-by-side stenting
205
PTBD was employed to thoroughly drain the target biliary branch; however, the incidence of recurrent tract cancer was relatively high [25, 26]. The EBD procedure has grad­ually improved and is currently the standard treatment. However, stent selection during preoperative EBD remains controversial. Most Japanese institutions employ endona­sobiliary drainage to reduce cholangitis before surgery, but this is uncomfortable for patients [27]. In addition, many high-volume cholangiocarcinoma surgery centers in Japan require patients to drink bile juice. Conventional PSs are standard for preoperative cases, but an inside stent placed above the papilla exhibited a longer cumulative TRBO [28]. This type of stent is promising, but more evidence is required.
Two endoscopic stenting methods are used when placing SEMSs in patients with unresectable hilar biliary malignan­cies: the stent-in-stent (SIS) and side-by-side (SBS) meth­ods. During the SIS method, it is sometimes difcult to place the second stent through the mesh. Certain SEMSs with loose or moveable portions have been developed to facilitate through-the-mesh placement. SBS is easier than SIS, and in some clinical trials, the initial placement success rate was similar to or slightly better than that of the SIS method. A problem with SBS placement is that a second/third SEMS delivery system passes beside the prior SEMS. When uncovered SEMSs are used, the techniques are different, but the clinical results have been similar [30].
Recent advances include slim-covered SEMSs and inside stents. Slim-covered SEMSs of thin diameter (6 mm) are

24.9 Hilar Stricture: Palliative Cases

placed in patients with hilar MBOs using the SBS method. Segmental cholangitis caused by obstruction of the biliary branch after covered SEMS placement has been of concern.
Drainage of 50% of the liver volume is required to preserve liver function and prevent ineffective stenting [29]. However, stent selection and placement are not standardized. Uncovered SEMSs exhibited longer TRBOs than those of PSs in some RCTs, but re-interventions were required when the uncovered SEMS became occluded. The Japanese clini­cal practice guidelines for bile duct cancer recommend the use of both PSs and metallic stents because many endosco­pists favor PSs.
However, the incidence thereof is not high [31]. Slim­covered SEMSs can be easily removed and exchanged. Inside stents are sutured above the papilla and have been reported to be easily removable (Fig.24.3). The inside stent also exhibits a longer cumulative TRBO than that of conven­tional PSs [32] (Fig. 24.4). However, many endoscopists remain concerned about removability, and large-scale stud­ies are warranted. No ideal stent for management of hilar MBO is yet available, thus requiring continued efforts.
206
a b
H. Isayama et al.
Fig. 24.4 Inside stent placement for the malignant hilar stricture case.
(a) X-ray image of inside stent placement above the papilla. (b) Inside stents. Suture for removal was attached to the distal site. Right side stent
24.10 Radiofrequency Ablation oftheBileDuct
Radiofrequency ablation of the bile duct was developed to improve stent TRBO [33]. Uncovered SEMSs exhibit tumor ingrowth via the stent mesh, and tumor ablation prior to SEMS placement delayed such ingrowth. Radiofrequency ablation prior to PS placement effectively prolonged the TRBO [34]. More studies and more evidence are needed.

24.11 Endoscopic Ultrasound-Guided Biliary Drainage

EUS-BD was developed as a salvage technique after dif­culty or failure of conventional endoscopic drainage. Initially, EUS-BD was indicated only for patients with unresectable
with deep angle indicates for the left and right-posterior branch. Left side stent indicates for right-anterior branch
MBOs, but currently, the indications are increasing. There are two principal types of EUS-BD: hepaticogastrostomy (EUS-HGS) and choledochogastrostomy (EUS-CDS) [2]. In EUS-HGS, a stula is created between the liver (the intrahe­patic bile duct) and the stomach. The EUS-CDS stula runs from the common hepatic duct/common bile duct to the duo­denum. This procedure is easier than EUS-HGS because the liver parenchyma is not penetrated. Recent Japanese clinical practice guidelines to ensure that EUS-BD is safe were pro­posed [35]. The procedure should be preferred to PTBD in various situations; however, very few reports on preoperative EUS-BD have appeared. Given recent developments in dedi­cated devices, two clinical trials have suggested that EUS-BD might serve as a primary drainage method [36, 37], being both effective and promising. The technique and devices must be developed further and standardized by referencing strong clinical and safety evidence.
24 Endoscopic Biliary Drainage andAssociated Procedures Required forPatients withMalignant Biliary Strictures
207

24.12 Conclusions

EBD remains the standard treatment for patients with biliary obstruction/stricture. As many procedures and stents are available, it is essential to choose them carefully. No stan­dard procedure or stent has yet emerged. EUS-BD is a rela­tively new biliary drainage modality that should become the drainage method of choice.
The English in this document has been checked by at least two professional editors, both native speakers of English. For a certicate, please see: http://www.textcheck.com/certi-
cate/QZ6lR6

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